Next generation sequencing (NGS) technologies have revolutionized our approach to studying the genetic basis of diseases and caused a paradigm shift in biological sciences. With the cost of whole genome sequencing (WGS) approaching the much-anticipated $1000 level, it is now affordable to sequence the whole genome of hundreds to thousands of patients or healthy people. As a result, our knowledge of genome and its regulation in health and disease has increased tremendously: following completion of the Human Genome Project (HGP), millions of variants and mutations have been identified and thousands of them have been associated with both inherited and sporadic diseases (1). So far, an overwhelming majority of clinical genomics studies have focused on the “exome” – protein-coding parts of the genome, mainly due to its much lower cost compared to WGS. ENCODE (Encyclopedia of DNA Elements) Project and similar efforts have provided peek into the functional organization of the genome (2), however, our knowledge of how genomic information is utilized is far from complete and limited. A better understanding of such fundamental principles of genome regulation will undoubtedly help us explain the molecular basis of pathologic disease states. The overarching goal of our research efforts is to unravel these principles within the context of nervous system disorders.

RESEARCH INTERESTS

Our research has two main approaches:

1. Identification of disease causing variants/mutations: targeted sequencing of functional elements, RNA-seq, WES, as well as WGS will be utilized in the analysis of patient samples.

2. Functional studies on identified variants in cell culture and animal models: CRISPR-Cas9 based genome editing is planned to be used extensively to generate models.

Autism Spectrum Disorders (ASDs) are among the most common neurodevelopmental disorders: 1 in 68 children in the USA are diagnosed with ASD (3). However, their clinical presentation is extremely heterogeneous, with deficits in social communication and interaction as the most prominent features (4). Recent genome-wide linkage and association studies have revealed that clinical heterogeneity is paralleled by genetic complexity. It has recently been shown that almost 70% of affected siblings carry different mutations (5), implicating that each child with ASD is “unique” and further studies are required to fully understand the molecular etiology of ASDs.

We are interested in identifying causal variants with the purpose of developing diagnostic and therapeutic tools.

Gliomas are the most common and deadliest type of primary brain tumors. Despite large-scale genomic efforts by consortiums such as The Cancer Genome Atlas (TCGA) have mapped the mutational landscape of gliomas (6,7),our knowledge on the processes of gliomagenesis is still scarce. On the other hand, Genome-Wide Association Studies (GWAS) have identified genomic loci/SNPs that are associated with increased glioma risk, however, the molecular basis of these associations are largely missing. Our studies aim to leverage information gained from these two different approaches to understanding the earliest steps of gliomagenesis.

RESEARCH HIGHLIGHTS

Our recent work on low-grade gliomas (LGGs) has focused on understanding the genetic basis of genetic predisposition to IDH-mutated gliomas, which comprise 70-80 % of LGGs. These studies were conducted by a multi-disciplinary approach that employed transcriptomic, proteomic, immunohistochemical, clinical and epidemiologic analyses of tumor and blood samples from LGG patients. A manuscript based on these studies is under review. Also, a TUBITAK 1001 grant has recently (2015) been awarded for 3 years to study the mechanistic basis of 8q24.21-associated genetic predisposition to glioma. Within this project, neural stem cell (NSC) lines are being edited by using the CRISPR-Cas9 system to obtain isogenic cell lines that differ at only the disease-associated variants/loci, in the absence and presence of IDH1-R132H mutation due to the strict association of these variants with IDH1/2 mutations. An integrated analysis of these cells will be carried out by 4C-seq, RNA-seq, enhancer assays, etc.